scholarly journals Low-dose IL-2 in the treatment of immune-related diseases

2021 ◽  
Vol 19 ◽  
pp. 205873922110399
Author(s):  
Jiakui Zhang ◽  
Yong Huang
Keyword(s):  
T Cells ◽  
Adverse Reactions ◽  
Low Dose ◽  
Interleukin 2 ◽  
Treg Cells ◽  
High Dose ◽  
Proliferation And Differentiation ◽  
Made In

Since the discovery of interleukin-2 (IL-2) in 1979, increasing attention has been focused on its role in regulating immune function. IL-2 has been found to play an important role in maintaining autoimmune tolerance, and it is essential for the proliferation and differentiation of regulatory T cells (Treg) cells. Other studies have found that the role of IL-2 in vivo is closely related to its concentration. Low-dose IL-2 selectively stimulates the proliferation of Treg cells in vivo, while high-dose IL-2 primarily promotes the proliferation of effector T cells. In view of these findings, an increasing number of studies have focused on the use of low-dose IL-2 in the treatment of immune-related diseases in recent years. The results have been encouraging, with mild adverse reactions. This article mainly focuses on the latest progress made in the IL-2 treatment of immune-related diseases and its regulatory effect on the immune status in different diseases, providing a reference for the rational clinical application of IL-2.

scholarly journals In vivo role of interleukin 4 in T cell tolerance induced by aqueous protein antigen.

1993 ◽  
Vol 177 (2) ◽  
pp. 457-463 ◽  
Author(s):  
H J Burstein ◽  
A K Abbas
Keyword(s):  
T Cells ◽  
T Cell ◽  
Interleukin 2 ◽  
Interleukin 4 ◽  
Th2 Cells ◽  
High Dose ◽  
Protein Antigens ◽  
Ifn Gamma

High doses of aqueous protein antigens induce a form of immunological tolerance in which interleukin 2 (IL-2)- and interferon gamma (IFN-gamma)-secreting T helper type 1 (Th1) cells are inhibited, but IL-4-secreting (Th2) cells are not. This is manifested by reduced proliferation of antigen-specific T cells upon in vitro restimulation, and marked suppression of specific antibody responses of the immunoglobulin (Ig)G2a, IgG2b, and IgG3 isotypes, but not of IgG1 and IgE. The role of the immunomodulatory cytokine IL-4 in this model of unresponsiveness to protein antigens has been examined. Administration of tolerizing antigen itself primes splenic CD4+ T cells for secretion of lymphokines, both IL-2 and IL-4. Neutralization of IL-4 in vivo with the anti-IL-4 antibody 11B11 during tolerance induction augments IFN-gamma production by T cells of tolerant mice, and reverses the suppression of IgG2a, IgG2b, and IgG3. This blockade of IL-4 function does not, however, restore the proliferative responses of T cells, suggesting that reduced T cell proliferation is due to direct T cell inactivation or anergy. Inhibiting the activity of IL-4 in vivo also inhibits the expansion of antigen-specific Th2-like cells, which are resistant to the induction of unresponsiveness. Thus, the immunologic consequences of high-dose tolerance are due to a combination of clonal T cell anergy and IL-4-mediated immune regulation.

scholarly journals Spatio-temporal biodistribution of 89Zr-oxine labeled huLym-1-A-BB3z-CAR T-cells by PET imaging in a preclinical tumor model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Naomi S. Sta Maria ◽  
Leslie A. Khawli ◽  
Vyshnavi Pachipulusu ◽  
Sharon W. Lin ◽  
Long Zheng ◽  
...  
Keyword(s):  
T Cells ◽  
Real Time ◽  
Pet Imaging ◽  
Dose Group ◽  
Low Dose ◽  
High Dose ◽  
Car T Cells ◽  
Nsg Mice ◽  
Car T

AbstractQuantitative in vivo monitoring of cell biodistribution offers assessment of treatment efficacy in real-time and can provide guidance for further optimization of chimeric antigen receptor (CAR) modified cell therapy. We evaluated the utility of a non-invasive, serial 89Zr-oxine PET imaging to assess optimal dosing for huLym-1-A-BB3z-CAR T-cell directed to Lym-1-positive Raji lymphoma xenograft in NOD Scid-IL2Rgammanull (NSG) mice. In vitro experiments showed no detrimental effects in cell health and function following 89Zr-oxine labeling. In vivo experiments employed simultaneous PET/MRI of Raji-bearing NSG mice on day 0 (3 h), 1, 2, and 5 after intravenous administration of low (1.87 ± 0.04 × 106 cells), middle (7.14 ± 0.45 × 106 cells), or high (16.83 ± 0.41 × 106 cells) cell dose. Biodistribution (%ID/g) in regions of interests defined over T1-weighted MRI, such as blood, bone, brain, liver, lungs, spleen, and tumor, were analyzed from PET images. Escalating doses of CAR T-cells resulted in dose-dependent %ID/g biodistributions in all regions. Middle and High dose groups showed significantly higher tumor %ID/g compared to Low dose group on day 2. Tumor-to-blood ratios showed the enhanced extravascular tumor uptake by day 2 in the Low dose group, while the Middle dose showed significant tumor accumulation starting on day 1 up to day 5. From these data obtained over time, it is apparent that intravenously administered CAR T-cells become trapped in the lung for 3–5 h and then migrate to the liver and spleen for up to 2–3 days. This surprising biodistribution data may be responsible for the inactivation of these cells before targeting solid tumors. Ex vivo biodistributions confirmed in vivo PET-derived biodistributions. According to these studies, we conclude that in vivo serial PET imaging with 89Zr-oxine labeled CAR T-cells provides real-time monitoring of biodistributions crucial for interpreting efficacy and guiding treatment in patient care.

scholarly journals In Vivo Role of Dendritic Cells in a Murine Model of Pulmonary Cryptococcosis

2006 ◽  
Vol 74 (7) ◽  
pp. 3817-3824 ◽  
Author(s):  
Karen L. Wozniak ◽  
Jatin M. Vyas ◽  
Stuart M. Levitz
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Ex Vivo ◽  
Interleukin 2 ◽  
Mouse Lung

ABSTRACT Dendritic cells (DC) have been shown to phagocytose and kill Cryptococcus neoformans in vitro and are believed to be important for inducing protective immunity against this organism. Exposure to C. neoformans occurs mainly by inhalation, and in this study we examined the in vivo interactions of C. neoformans with DC in the lung. Fluorescently labeled live C. neoformans and heat-killed C. neoformans were administered intranasally to C57BL/6 mice. At specific times postinoculation, mice were sacrificed, and lungs were removed. Single-cell suspensions of lung cells were prepared, stained, and analyzed by microscopy and flow cytometry. Within 2 h postinoculation, fluorescently labeled C. neoformans had been internalized by DC, macrophages, and neutrophils in the mouse lung. Additionally, lung DC from mice infected for 7 days showed increased expression of the maturation markers CD80, CD86, and major histocompatibility complex class II. Finally, ex vivo incubation of lung DC from infected mice with Cryptococcus-specific T cells resulted in increased interleukin-2 production compared to the production by DC from naïve mice, suggesting that there was antigen-specific T-cell activation. This study demonstrated that DC in the lung are capable of phagocytosing Cryptococcus in vivo and presenting antigen to C. neoformans-specific T cells ex vivo, suggesting that these cells have roles in innate and adaptive pulmonary defenses against cryptococcosis.

scholarly journals IL-2 administration increases CD4+CD25hi Foxp3+ regulatory T cells in cancer patients

Blood ◽  
2006 ◽  
Vol 107 (6) ◽  
pp. 2409-2414 ◽  
Author(s):  
Mojgan Ahmadzadeh ◽  
Steven A. Rosenberg
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Interleukin 2 ◽  
Selective Inhibition ◽  
High Dose ◽  
Protein Levels ◽  
And Function ◽  
The Impact

Abstract Interleukin-2 (IL-2) is historically known as a T-cell growth factor. Accumulating evidence from knockout mice suggests that IL-2 is crucial for the homeostasis and function of CD4+CD25+ regulatory T cells in vivo. However, the impact of administered IL-2 in an immune intact host has not been studied in rodents or humans. Here, we studied the impact of IL-2 administration on the frequency and function of human CD4+CD25hi T cells in immune intact patients with melanoma or renal cancer. We found that the frequency of CD4+CD25hi T cells was significantly increased after IL-2 treatment, and these cells expressed phenotypic markers associated with regulatory T cells. In addition, both transcript and protein levels of Foxp3, a transcription factor exclusively expressed on regulatory T cells, were consistently increased in CD4 T cells following IL-2 treatment. Functional analysis of the increased number of CD4+CD25hi T cells revealed that this population exhibited potent suppressive activity in vitro. Collectively, our results demonstrate that administration of high-dose IL-2 increased the frequency of circulating CD4+CD25hi Foxp3+ regulatory T cells. Our findings suggest that selective inhibition of IL-2-mediated enhancement of regulatory T cells may improve the therapeutic effectiveness of IL-2 administration. (Blood. 2006;107:2409-2414)

scholarly journals Essential role of the interleukin 2-interleukin 2 receptor pathway in thymocyte maturation in vivo.

1988 ◽  
Vol 168 (5) ◽  
pp. 1741-1747 ◽  
Author(s):  
L Tentori ◽  
D L Longo ◽  
J C Zuñiga-Pflucker ◽  
C Wing ◽  
A M Kruisbeek
Keyword(s):  
T Cells ◽  
Essential Role ◽  
Interleukin 2 ◽  
Beta Chain ◽  
Thymocyte Development ◽  
Single Positive ◽  
Thymocyte Differentiation ◽  
Single Positive Cell

The role of the IL-2-IL-2-R pathway in thymocyte differentiation in vivo is unknown. We have examined fetal thymocyte development in vivo, under conditions where all IL-2-R were saturated from day 13 of gestation with anti-IL-2-R mAbs that were previously shown to render mature T cells unable to respond to IL-2. This produced a dramatic change in the composition of developing T cells: thymocytes from day 1 neonatal mice born to anti-IL-2-R-treated mothers did not contain CD4+ or CD8+ single-positive cell populations. In addition, no generation of surface TCR beta chain-expressing T cells or antigen-reactive functional T cells occurred in treated mice. These data suggest that IL-2-IL-2-R interactions provide signals crucial to in vivo intrathymic development of mature T cells.

scholarly journals Immunotherapy of a murine tumor with interleukin 2. Increased sensitivity after MHC class I gene transfection.

1987 ◽  
Vol 166 (6) ◽  
pp. 1716-1733 ◽  
Author(s):  
J S Weber ◽  
G Jay ◽  
K Tanaka ◽  
S A Rosenberg
Keyword(s):  
T Cells ◽  
Mhc Class I ◽  
Interleukin 2 ◽  
Class I ◽  
High Dose ◽  
Class I Mhc ◽  
High Doses ◽  
I Gene

We have shown that two weakly immunogenic MCA sarcomas developed in our laboratory that are sensitive to high-dose IL-2 immunotherapy express class I MHC in vivo and in vitro. Two nonimmunogenic MCA sarcomas are relatively insensitive to IL-2 therapy and express minimal or no class I MHC molecules in vivo and in vitro. To study the role of MHC in the therapy of tumors with IL-2, a class I-deficient murine melanoma, B16BL6, was transfected with the Kb class I gene. Expression of class I MHC rendered B16BL6 advanced pulmonary macrometastases sensitive to IL-2 immunotherapy. 3-d micrometastases of CL8-2, a class I transfected clone of B16BL6, were significantly more sensitive to IL-2 therapy than a control nontransfected line. Expression of Iak, a class II MHC molecule, had no effect on IL-2 therapy of transfectant pulmonary micrometastases in F1 mice. By using lymphocyte subset depletion with mAbs directed against Lyt-2, therapy of class I transfectant macrometastases with high-dose IL-2 was shown to involve an Lyt-2 cell. In contrast, regression of micrometastases treated with low-dose IL-2 involved Lyt-2+ cells, but regression mediated by high doses of IL-2 did not. We hypothesize that both LAK and Lyt-2+ T cells effect IL-2-mediated elimination of micrometastases, but only Lyt-2+ T cells are involved in macrometastatic regression. Low doses of IL-2 stimulate Lyt-2+ cells to eliminate class I-expressing micrometastases, but high doses of IL-2 can recruit LAK cells to mediate regression of micrometastases independent of class I expression. Only high-dose IL-2, mediating its effect predominantly via Lyt-2+ cells, is capable of impacting on MHC class I-expressing macrometastases. Macrometastases devoid of class I MHC antigens appear to be resistant to IL-2 therapy.

scholarly journals Interferon Regulatory Factor 4 Is a Key Factor in Regulation of Thelper Cell Polarization in Graft-Versus-Host Disease

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3313-3313
Author(s):  
Jochen T Frueh ◽  
Bushra Rais ◽  
Daniele Yumi Sunaga-Franze ◽  
Katja Stein ◽  
Sascha Sauer ◽  
...  
Keyword(s):  
T Cells ◽  
Treg Cells ◽  
Cell Polarization ◽  
Th Cells ◽  
Th Cell ◽  
Target Organs ◽  
Donor T Cells ◽  
Interferon Regulatory Factor 4

Abstract Introduction: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective therapy for severe malignant diseases. Following allo-HSCT, donor T cells are the driving force for eradication of the remaining malignant cells known as graft-versus-tumor (GVT) effect. However, these alloreactive T cells are also responsible for induction of graft-versus-host disease (GVHD). To date, the role of the different Thelper (Th) subsets in the pathogenesis of GVHD is not completely understood. Interestingly, these subsets share expression of a transcription factor called Interferon Regulatory Factor 4 (IRF4), which is proposed as a master regulator of cell fate decision of T cells. This project aims to analyze the role of IRF4 in Th cell polarization during the development of GVHD. Methods: In mixed lymphocyte reaction (MLR), we analyzed the proliferation capacity of CFSE-labelled IRF4-deficient (IRF4-/-) T cells upon allogeneic stimulation by LPS-induced dendritic cells (DC). For analyzing the impact of IRF4 in vivo, we used previously published complete MHC-mismatched murine GVHD model (Ullrich et al., J Clin Invest, 2018). Herein, we investigated the alloreactivity of the transplanted donor T cells towards GVHD target organs with focus on colonic tissue. Additionally, RNA sequencing of re-isolated and high purity FACS-sorted donor Th cells were performed to get a deep insight into the IRF4-mediated regulation of Th cell polarization. Results: In the MLR setting, reduced CFSE dilution indicated a diminished proliferative capacity of both CD4+ and CD8+ IRF4-/- T cells compared to the corresponding WT (IRF4+/+) T cell subsets upon allogeneic stimulation (Figure 1A). Furthermore, while alloreactive WT CD4+ T cells induced severe forms of GVHD in vivo, clinical GVHD symptoms of recipients transplanted with IRF4-/- CD4+ T cells were significantly reduced and these mice showed prolonged overall survival (Figure 1B). Analyzing the mechanism, we found that the frequency of in vivo circulating donorCD4+ IRF4-/- T cells was reduced compared to transplanted WT Th cells, especially in the GVHD target organs such as the colon. However, IRF4-/- Th cells persisted in spleen, lung and colon even if they showed a reduced proliferative capacity. In line with that, colonoscopy of mice transplanted with IRF4-deficient Th cells revealed a significant reduction of GVHD associated colitis. Transcriptome analysis of re-isolated and high purity FACS-sorted donor Th cells depicted an altered gene expression profile in donor IRF4-/- Th cells compared to donor WT Th cells. Specifically, master regulators of Th cell subsets like T-bet (Th1), RORγt (Th17) and to some amount also GATA-3 (Th2) were downregulated in donor IRF4-/- Th cells whereas FoxP3, the master regulator of regulatory T cells (Treg cells), was significantly upregulated. Along the same line cytokines associated with Th1, Th2 and Th17 cell subsets such as IFN-γ, IL-21, IL-6 and IL-13 were also significantly downregulated. Besides genes that are associated with Treg cell function like Helios, FR4 (folate receptor 4) and Neuropilin 1, a transcriptional repressor, Bach2, which regulates the formation of Treg cells and suppresses Th1, Th2 and Th17 subset differentiation was highly upregulated (Tsukumo et al., Proc Natl Acad Sci U S A, 2013; Kim et al., J Immunol, 2014 ; Roychoudhuri et al., Nature, 2013 ; Vahedi et al., Nature, 2015). Along with the upregulation of Bach2 and the significant downregulation of Blimp1, another transcriptional repressor involved in T cell homeostasis and function as well as direct target of Bach2, we hypothesize that IRF4 might compete with BACH2 for the binding to BATF. These hypotheses also rely on our previous finding of BATF as critical mediator of GVHD colitis and are currently under further evaluation (Ullrich et al., J Clin Invest, 2018). Conclusion: In summary, our results indicate that IRF4 plays a key role in regulation of the Th cell polarization and therefore also in the development of GVHD. Thus, IRF4 in its interplay with BATF might be considered as a clinically relevant target for GVHD therapy. Disclosures No relevant conflicts of interest to declare.

Role of STAT3 in Immunoregulatory Function of Human Bone Marrow-Derived Mesenchymal Stem Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3637-3637
Author(s):  
Jinsun Yoon ◽  
Seoju Kim ◽  
Eun Shil Kim ◽  
Byoung Kook Kim ◽  
Young Lee
Keyword(s):  
T Cells ◽  
Conflicts Of Interest ◽  
Hematologic Malignancies ◽  
Treg Cells ◽  
Human Mscs ◽  
Hematopoietic Stem ◽  
The One

Abstract Abstract 3637 Poster Board III-573 The one of the best curative treatment modality in hematologic malignancies is an allogeneic hematopoietic stem cell transplantation (HSCT). However, graft-versus-host disease (GVHD) is a major obstacle of allogeneic HSCT. BM derived human MSCs are known to have immunoregulatory effect in vitro and in vivo via inhibiting alloreactive T lymphocytes, leading to their clinical use for the prevention of GVHD in HSCT. However, the molecular mechanism of immunoregulatory effect of human MSCs is not fully understood. In this study, the signaling of immunoregulatory effect was investigated by co-culture of human MSCs with lymphocytes. The proliferation of allogeneic T cells was inhibited by MSCs. Among the STATs, STAT3 was a key molecule in MLR co-cultured with MSCs. STAT3 siRNA treated MSCs did not inhibit the lymphocyte proliferation. After MSCs were trasnsfected with STAT3 plasmid, the fraction of CD4+CD25+FOXP3+ cells (Treg cells) were increased, while the fraction of CD4+, CD8+, CD25+ was decreased. In addition, Th1-related cytokines (IL-2, IL-12 and INF-γ) and Th17-related cytokines (IL-6, IL-17 and IL-21) were down-regulated, and Th2-related cytokines (GATA-3, IL-4 and IL-10) were up-regulated in MLR co-cultured with STAT3-ablated MSCs, while vice versa in MLR co-cultured with STAT3-transfected MSCs. Furthermore, ELISA showed that concentration of Th1-related cytokine (IL-2) in the supernatant of MLR co-cultured with STAT3-ablated MSCs was higher than that of control; while concentration of Th2-related cytokine (IL-4) was lower than that of control. These results suggested that induction of Th1 to Th2 shift by MSCs might be mediated via STAT3 molecule. In summary, STAT3 may be an indispensable molecule in the immunoregulatory effect in human MSCs via modulation of regulatory T cells. Disclosures: No relevant conflicts of interest to declare.

In Vitro expanded STAT1−/− Regulatory T Cells Prevent Acute Graft Versus Host Disease (GVHD) and Promote Donor Cell Engraftment In Allogeneic Fully MHC-Mismatched Bone Marrow Transplant

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 732-732
Author(s):  
Huihui Ma ◽  
Caisheng Lu ◽  
Judy Ziegler ◽  
Suzanne Lentzsch ◽  
Markus Y Mapara
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Cells ◽  
Donor Cell ◽  
Treg Cells ◽  
Cell Engraftment ◽  
Lethal Irradiation

Abstract Abstract 732 Treg cells have been recognized as critical regulators of the immune response and shown to prevent the development of GVHD. However, little is known about of the role of STAT1 signaling in Treg cells during the development of GVHD. In this study, we tried to investigate how STAT1 signaling controls donor Treg development and function in the setting of GVHD. For this purpose we studied the role of STAT1 in natural and inducible Treg (nTreg and iTreg, respectively). To better understand the influence of STAT1-deficiency on the proliferation of nTreg cells, purified splenic STAT1−/− or STAT1+/+ CD4+CD25+ cells were labeled with Carboxyfluorescein succinimidyl ester (CFSE) and cultured on anti-CD3 coated plates in the presence of anti-CD28 and IL-2 for 3 days and analyzed for proliferation and viability. After 72h of in vitro culture 50% of the STAT1+/+ starting population were no longer viable compared to only 10% of STAT1−/− cells. Furthermore, we noted a significantly increased expansion of STAT1-deficient CD4+CD25+Foxp3+ Treg cells compared to STAT1+/+ Treg cells (p<0.001). In line with these findings, STAT1-deficiency resulted in a significantly higher proportion of CFSElo cells indicating vigorous proliferation (85% Foxp3+CFSElo in STAT1−/− compared to only 65% Foxp3+CFSElo in STAT1+/+ Treg cells. Furthermore, at the end of the culture 30% of the STAT1+/+ CD4+CD25+ population were Foxp3-negative compared to only 10% of the STAT1−/− cells. We next determined the impact of STAT1 on the generation of iTreg cells in vitro. For this purpose CD4+CD25− cells from STAT1−/− or STAT1+/+ mice were cultured for 3 days on anti-CD3 coated plates in the presence of anti-CD28 antibodies, hTGF-β, mIL-2, anti-IFN-γ and anti-IL-4 for 3 days. Compared to STAT1+/+, we observed significantly enhanced generation of iTregs from STAT1−/− splenocytes (19.9%±3.0% vs. 10.6%±1.3%, p=0.008). We then performed studies to assess the in vivo generation of iTreg. For that purpose BALB/c mice were reconstituted with T Cell Depleted (TCD) 129.STAT1+/+Bone Marrow Cells (BMC) following lethal irradiation and recipients were co-injected with CD4+CD25− cells purified from either 129.STAT1+/+ or 129.STAT1−/− splenocytes. We again noted a significantly higher proportion of CD4+CD25+ Foxp3+ cells in recipients of CD4+CD25−STAT1−/− cells compared to recipients of STAT1+/+ T cells indicating a significantly increased conversion of CD4+CD25- cells into Treg cells. To confirm the in vitro results we tested the functional ability of in vitro expanded (using anti-CD3, anti-CD28, IL-2 and TGF-β) STAT1+/+ or STAT1−/− Treg cells to block induction of GVHD. GVHD was induced in BALB/c mice following lethal irradiation (800rad) and fully MHC-mismatched BMT using 129.STAT1+/+ bone marrow cells plus 129.STAT+/+ conventional T cells (Tcon). Animals were co-injected with expanded Treg cells from either 129.STAT1+/+ or 129.STAT1−/− donors at a ratio of 1:1 or 1:4 (Treg:Tcon). STAT1−/− or STAT1+/+ Treg cells were equipotent in completely preventing GVHD mortality. However, compared to recipients of STAT1+/+ Treg recipients of STAT1−/− Treg showed reduced signs of GVHD morbidity as determined by a significantly improved weight development. Furthermore, recipients of STAT1−/− Treg showed significantly increased donor cell engraftment compared to recipients of STAT1+/+Treg (donor CD4+ [87% vs. 60%, p=0.03], CD8+[99% vs. 96%, p=0.04], Mac1+[96% vs. 77%, p=0.02] and B220+[100% vs. 96%, p=0.007]) cells in the recipient spleen. These observations clearly demonstrate that STAT1 is a critical regulator of Treg cell development and expansion and that targeting STAT1 in CD4+ T cells may facilitate in vitro and in vivo generation/expansion of Treg cells for therapeutic use in GVHD while also promoting donor cell engraftment. Disclosures: Lentzsch: Celgene Corp: Research Funding. Mapara:Resolvyx: Research Funding; Gentium: stocks.

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